Stress-specific activation and repression of heat shock factors 1 and 2

Vertebrate cells express a family of heat shock transcription factors (HSF1 to HSF4) that coordinate the inducible regulation of heat shock genes in r esponse to diverse signals. HSF1 is potent and activated rapidly though tra nsiently by heat shock, whereas HSF2 is a less active transcriptional regul ator but can retain its DNA binding properties for extended periods. Conseq uently, the differential activation of HSF1 and HSF2 by various stresses ma y be critical for cells to Survive repeated and diverse stress challenges a nd to provide a mechanism for more precise regulation of heat shock gene ex pression. Here we show, using a novel DNA binding and detection assay, that HSFI and HSF2 are coactivated to different levels in response to a range o f conditions that cause cell stress. Above a low basal activity of both HSF s, heat shock preferentially activates HSF1, whereas the amino acid analogu e azetidine or the proteasome inhibitor MG132 coactivates both HSFs to diff erent levels and hemin preferentially induces HSF2. Unexpectedly, we also f ound that heat shock has dramatic adverse effects on HSF2 that lead to its reversible inactivation coincident with relocalization from the nucleus. Th e reversible inactivation of HSF2 is specific to heat shock and does not oc cur with other stressors or in cells expressing high levels of heat shock p roteins. These results reveal that HSF2 activity is negatively regulated by heat and suggest a role for heat shock proteins in the positive regulation of HSF2.